Transcript E-2 Ethinyl Estradiol

E-2 Ethinyl Estradiol
Joshua Nazeck
Aquatic Toxicology
Dr. Mason
Structure of the Compound and Physical and
Chemical Properties
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Synthetic derivative of natural
estrogen estradiol
High estrogen receptor
potency
Molecular formula
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C20H24O2
Quickly absorbed when taken
orally (most common form of
administration)
Odorless
Mol. Weight=296.41 g/mole
Physical and Chemical Properties
continued
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Significance of the substitution at C17 with the estrane steroid.
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Metabolized in the liver by means of Cytochrome P450 3A4
isoenzyme and CYP P450 2A6
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Estradiol is quickly degraded by liver, substitution allows for resistance
to this degradation
Targets the estrogen receptor and Orphan nuclear receptor PXR
variations occur in the absorption process and can have interactions
with antibiotics
Fully bound to plasma albumin
Metabolized via hydroxilation of aromatic ring
Released into environment as a xenoestrogen via urine and feces.
Uses and Application, Production History etc
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In almost all forms of modern combined oral
contraceptives
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One of the most commonly used medications
Synthesized by Hanz Herloff Inhoffen in 1938
FDA approved the drug on June 25th 1943
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1st marketed by Schering as Estinyl
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FDA approval of estinyl withdrawn in 2004 due to
discontinuation
Found under 56 different brand names and 46
different mixtures
Applications continued
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Used for treatment of vasomotor
symptoms associated with menopause,
female hypogonadism, prostatic
carcinoma-palliative therapy, breast
cancer, and oral and emergency
contraceptive
Mode of Entry in Aquatic
Environment
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Urban runoff and wastewater effluent are the main
sources of entry into the aquatic environment
Enters system via human urine and fecal matter
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wastewater treatment facilities treat the water before dumping
back into aquatic environment
Not fully degraded and therefore large amounts still present in
wastewater
One of most commonly used medications we therefore
would expect this to be found in large quantities at sites
of wastewater runoff and highly developed areas.
Chemical reactivity with water,
chemical speciation, physical
half-life etc
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Found to be soluble very slightly soluble in
water.
Experimental water solubility = 6.77 e-3 mg/L
Physical half life 36 ± 13 hours.
Has drug interactions with a large number of
other drugs on the market
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Too many drugs to note as well as varying
interactions ranging from increasing effect and
toxicity of theophylline and other toxins, to increased
thrombotic risk due to estrogen
Toxicity to aquatic life
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The toxicity of ethinyl estradiol is relatively minor according to the
FDA website.
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Mouse LD 50= 1737 mg/kg.
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Symptoms include nausea vomiting and withdrawal bleeding in females
However studies have been conducted concerning the feminization
of marine organisms recently on a large scale
Up to 38% of Chinook Salmon found in the Sacramento and San
Joaquin rivers were found to exhibit signs of
feminization(http://www.ce.berkeley.edu/~sedlak/CALFEDwebsite.ht
m#desbrow1998).
Ehtinyl Estradiol was found to be one of the many steroid
contaminants in this river system
Feminization occurs for the most part during larval development
Impacts reproductive potential of marine organisms by essentially
limiting the number of males present in a population.
Toxicity to aquatic life continued
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Potentially a very large problem
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Ethinyl estradiol is most commonly found in sublethal
concentrations
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However even sublethal concentrations when present for
multiple generations have negative effects.
A study on the development of amphipods
showed significant results concerning
feminization and adverse effects associated with
ethinyl estradiol concentrations
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Hermaphroditism, disturbed maturation of germ cells,
and disturbed spermatogenesis were found in all post
F1 generation males exposed to EE
Toxic effects noted
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Feminization of marine organisms
Disturbed development and lowered fecundity
Altered courtship behaviors in some fish
(http://www.wef.org/NR/rdonlyres/F362B57D7F25-45AA-96D066938800917A/0/MDWolfand.pdf)
LD 50=1737 mg/kg in mice
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Nausea, vomitting, and withdrawal bleeding in
females
Mode of entry into organisms
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Non-aquatic organisms: usually enters as oral
medication
Aquatic organisms:
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Absorption through gills or other rspiratory or
absoprtive surface
Found in wastewater effluent and urban runoff
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When this enters aquatic environment organisms are
then subject to high levels of a steroid modified
estrogen
Molecular mode of toxic
interaction
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Ehtinyl estradiol is lipid soluble
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Diffuses easily through cell membrane
Diffuse into target cells and interact with protein
receptor there.
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Target Cells: female reproductive tract, mammary
gland, hypothalamus, and the pituitary gland
Then increase hepatic synthesis of sex hormone
binding globulin, thyroid binding globulin and other
serum proteins
Molecular Mode of Interaction
Continued
Suppresses follicle-stimulating hormone from the
anterior pituitary
 Combination of an estrogen with a progestin
suppresses the hypothalamic-pituitary system
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Decreases secretion of gonadotropin-releasing hormone
Biochemical metabolism and
breakdown
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Metabolized via Cyp P450 3A4 and Cyp
P450 2A6
Aromatic C ring broken down by
hydroxilation
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After breakdown in the liver the estradiol bind
to the estrogen receptors
Remaining ethinyl estradiol is excreted in
the form of human waste
Works Cited
1- http://www.drugbank.ca/cgi-bin/getCard.cgi?CARD=DB00977.txt
2- Vandenburgh, Gurt et al. Effects of 17 -ethinylestradiol on sexual development of the
amphipod Hyalella azteca. Ecotoxicolgy and Environmental Safety. Vol 54 Issue 2.
2003 216-222
3- Material Safety Data Sheet Ethinyl Estradiol. Science Lab.com, Updated 2005
4- Wolfland, Jordan. Active Ingredient in Oral Contraceptives (17-ethinylestradiol) Alters
Male Competitive Courtship Behaviors and Secondary Sexual Characteristics in
Fathead Minnows (Pimephales promelas). Journal of the US SJWP. Pgs 42-52.
http://www.wef.org/NR/rdonlyres/F362B57D-7F25-45AA-96D066938800917A/0/MDWolfand.pdf
5- Fergus, John. Benitez, J. Ethinylestradiol. INTOX-10 Meeting. ICPBS INCHEM 1997.
http://www.inchem.org/documents/pims/pharm/pim221.htm#SectionTitle:5.5%20%
20Parenteral